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Urotensin-II Ligands: an Overview from Peptide to Nonpeptide Structures

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Urotensin-II Ligands: an Overview from Peptide to Nonpeptide Structures Hindawi Publishing Corporation Journal of Amino Acids Volume 2013, Article ID 979016, 15 pages http://dx.doi.org/10.1155/2013/979016 Review Article Urotensin-II Ligands: An Overview from Peptide to Nonpeptide Structures Francesco Merlino,1 Salvatore Di Maro,1 Ali Munaim Yousif,1 Michele Caraglia,2 and Paolo Grieco1 1 Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy 2 Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy Correspondence should be addressed to Paolo Grieco; [email protected] Received 2 December 2012; Accepted 14 January 2013 Academic Editor: Giuseppe De Rosa Copyright © 2013 Francesco Merlino et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Urotensin-II was originally isolated from the goby urophysis in the 1960s as a vasoactive peptide with a prominent role in cardiovascular homeostasis. The identification of human isoform of urotensin-II and its specific UT receptor by Ames et al. in1999 led to investigating the putative role of the interaction U-II/UT receptor in multiple pathophysiological effects in humans. Since urotensin-II is widely expressed in several peripheral tissues including cardiovascular system, the design and development of novel urotensin-II analogues can improve knowledge about structure-activity relationships (SAR). In particular, since the modulation of the U-II system offers a great potential for therapeutic strategies related to the treatment of several diseases, like cardiovascular diseases, the research of selective and potent ligands at UT receptor is more fascinating. In this paper, we review the developments of peptide and nonpeptide U-II structures so far developed in order to contribute also to a more rational and detectable design and synthesis of new molecules with high affinity at the UT receptor. 1. Introduction species, the cyclic hexapeptide sequence, c[Cys-Phe-Trp- Lys-Tyr-Cys], is conserved in all isoforms (Figure 1,orange Urotensin-II (U-II) belongs to a series of regulatory neu- residues). ropeptides first isolated from the urophysis of the teleost fish The length of urotensin-II peptides is variable across Gillichthys mirabilis by Karl Lederis and Howard Bern in the species and it ranged from 17 amino acid residues in mice 1960s. This cyclic peptide derived from goby fish, H-Ala- to 11 in humans, depending on the proteolytic cleavages Gly-Thr-Ala-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH, was that occur in precursors. The N-terminus region of U-II originally characterized on the basis of its interesting smooth is highly variable among animal species [5], whereas the muscle contracting and hypertensive effects. It has been long C-terminal amino acids, organized in a disulphide-linked considered that U-II was exclusively produced by the fish cyclic array, c[Cys-Phe-Trp-Lys-Tyr-Cys], are continuously urophysis [1].However,theidentificationofU-IIfromthe conserved from species to species, suggesting their primary brain of a frog [2, 3] has shown that the cDNA encoding role in the biological activity [6]. In addition, the goby prepro-U-II exists in several species of vertebrates. Moreover, isoform of U-II exhibits some structural similarities with thegeneisexpressednotonlyinthecaudalportionofthe somatostatin-14 concerning especially the presence of a spinal cord but also in brain neurones, from frogs to humans disulphide-linked cyclic core at their C-terminus portion [4]. In fact, urotensin-II isopeptides are present in several containing the biologically active domain Phe-Trp-Lys [7]. species of vertebrates, and although the amino acid sequence Moreover, the characterization of cDNA encoding carp pro- in the N-terminus of urotensin-II peptides diverges across U-II has shown that the U-II and somatostatin-14 precursors 2 Journal of Amino Acids share a common structure organization since the active altered since pathogenesis of several cardiovascular disorders peptides are both located at the C-terminal portion of the provokes an upregulation of UT receptor and of U-II resulting precursors [8]. Later, once the UT receptor was identified as a in vasoconstriction. member of somatostatin receptor family, some somatostatin- To date, findings in molecules with high affinity tothe like peptides containing a disulphide bridge, such as human urotensin-II system has led to discovering new ligands, melanin-concentrating hormone (MCH), somatostatin-14, peptide, and nonpeptide analogues. This review is aimed at cortistatin-14, and octreotide, were screened on UT receptor investigating the structure-activity relationship on urotensin- in order to compare the resulting biological activities with II system by analyzing peptide and nonpeptide structures so that of the endogenous U-II [9]. By these observations it was far developed in order to contribute also to a more rational established that U-II represented the only endogenous ligand and detectable design and synthesis of new molecules with with high affinity for the somatostatin-like receptor named high affinity at the UT receptor. UT receptor. The human UT-II (hU-II) is a cyclic undecapeptide, H- Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH, rec- 2. SAR Studies on U-II ognized as the natural ligand of an orphan G-protein coupled receptor, first named as a rat receptor with high affinity The potential therapeutic application of urotensin-II system for U-II, GPR14 [10–12]. Subsequently, a human G-protein has continuously stimulated structure-activity relationship coupled receptor showing 75% similarity to the orphan rat studies (SARs), which could elucidate the structural features receptor was cloned and renamed UT receptor by IUPHAR of this important hormone. On the other hand, the discovery [13]. The role of UT receptor has been continuously inves- of new analogues acting as agonist or antagonist is extremely tigated and nowadays it is commonly accepted that it is important to explore the physiological role of hU-II. First widely distributed in the CNS and in different peripheral structural studies performed on U-II by nuclear magnetic tissues including cardiovascular system [14], kidney, blad- resonance (NMR) spectroscopy [23–25] have revealed that der, prostate, and adrenal gland [10, 15–17]. This exten- the peptide adopted a preferential conformation both in sive expression has revealed the multiple pathophysiological DMSO and water solution, which did not show any classical effects mediated by the hUT/UT receptor interaction such as secondary structures. Amino acids in the core region of U- II are identified in a highly compact conformation with the cardiovascular disorders (heart failure, cardiac remodelling, 4 7 8 and atherosclerosis), smooth muscle cell proliferation, renal formation of a hydrophobic pocket, in which Ala ,Phe ,Trp , 12 disease, diabetes, and tumour growth [18]. Nevertheless, UT and Val are projected on the same side of the molecule receptor is especially expressed in vascular smooth muscle, being at least in part important residues for the binding site. endothelium,andmyocardiumandplaysakeyroleinthe In contrast, hU-II and some analogues resulted to be fold in regulation of the cardiovascular homeostasis. Furthermore, defined secondary structure when dissolved in SDS solution, this receptor has much structural homology to members of a membrane mimetic environment [26]. the somatostatin and receptor family and it could be activated Subsequently, with the aim of investigating the role played by somatostatin-14 and cortistatin at micromolar doses [10]. by the exocyclic region in the receptor interaction, a series The gene coding for the UT receptor has been located in of truncated peptides related to hU-II has been investigated. chromosome 17q25.3 [19]. Truncation studies are of prime importance for the detection The hU-II binds with high affinity to this receptor, result- of the minimal sequence of peptide required to retain the bio- ing in intracellular calcium mobilization via phospholipase logical activity. The effect of sequential deletion of exocyclic C-dependent increase in inositol phosphates. In isolated rat residues from N- or C-termini in hU-II sequence does not thoracic aorta fragments hU-II induces contraction mediated appear to be significant in the calcium-mobilizing potency by two distinct tonic and phasic components. However, its and efficacy, whereas the removal of any residue that belongs vasoconstrictor activity is well observed in primate arteries, to the cyclic region determines reduction or total absence of in which it causes a concentration-dependent contraction thebiologicalactivity.Theshortestandfullypotentsequence of isolated arterial rings with an EC50 valuelessthan1nM, of U-II was individuated in the octapeptide U-II(4–11),H- meaning a 10-fold more potency than endothelin-1. However, Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]Val-OH, that preserves the the in vivo effects can depend on the species, type of potency at the human UT receptor, showing similarity to blood vessel, concentration of U-II, route of administration, somatostatin-14 in which truncation of the segment led to and results of tissue and species in exam, and they can active analogues. be also contradictory. Accordingly, the peptide also elicits The importance of a free amino group in the N-terminal vasodilatory effects on the small arteries of rats and on the of the resulted
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